Role of Lysine Lactylation in Pulmonary Health

Lysine lactylation, a recently identified post-translational modification, plays a significant role in pulmonary health by influencing various cellular processes. This modification occurs when a lactyl group is added to lysine residues in proteins, influencing gene transcription and protein function. Importantly, lysine lactylation has been implicated in the progression of pulmonary diseases, including lung cancer and inflammatory conditions.

Research indicates that the respiratory system exhibits a unique metabolic profile characterized by a shift towards glycolytic metabolism, particularly in the context of diseases such as asthma and pulmonary fibrosis. This metabolic reprogramming is often accompanied by an overproduction of lactate, which serves as a substrate for lysine lactylation. Elevated lactate levels have been shown to enhance histone lactylation, thereby modulating the expression of genes involved in inflammation and immune responses (Wang et al., 2025).

As the lungs also function as vital immune organs, the interplay between lysine lactylation and the immune response is crucial. Lactate-induced histone modifications have been linked to the activation of pro-inflammatory pathways, suggesting that targeting lysine lactylation may offer novel therapeutic strategies for treating pulmonary diseases characterized by excessive inflammation (Wang et al., 2025).

Mechanisms of Lactylation in Lung Cancer Progression

Lung cancer, specifically non-small cell lung cancer (NSCLC), is a leading cause of cancer-related mortality worldwide. The metabolic adaptations observed in lung cancer cells, such as increased glycolysis, lead to the accumulation of lactate in the tumor microenvironment. This lactate not only fuels cancer cell metabolism but also promotes lysine lactylation, which can activate oncogenic pathways.

Histone lactylation has been identified as a critical mechanism in lung cancer progression. For instance, the enrichment of lactylated histones at the promoters of glycolytic enzymes enhances their expression, thus supporting the metabolic demands of rapidly proliferating tumor cells (Wang et al., 2025). Additionally, studies have demonstrated that elevated lactate levels can drive the expression of transcription factors such as SOX9, which is associated with stemness, migration, and invasion in NSCLC cells (Wang et al., 2025).

The dual role of lactylation in both tumor promotion and immune evasion provides insights into potential therapeutic targets. By understanding the molecular underpinnings of lysine lactylation in lung cancer, researchers can devise strategies to inhibit this modification and potentially halt tumor progression.

Histone and Non-Histone Lactylation: Implications for Therapy

The implications of lysine lactylation extend beyond histone modifications to include non-histone proteins. Lactylation can affect the activity, stability, and interactions of various non-histone proteins, thereby influencing cellular behavior in both cancer and pulmonary diseases.

Histone Lactylation

Histone lactylation, particularly at specific lysine residues, alters chromatin dynamics and gene expression. This modification has been shown to enhance the transcription of genes involved in inflammation and immune regulation, thereby contributing to the pathological state in various pulmonary diseases (Wang et al., 2025).

Non-Histone Lactylation

Non-histone proteins, including metabolic enzymes and transcription factors, are also subject to lactylation. For example, the lactylation of glycolytic enzymes can decrease their activity, leading to an adaptive metabolic response in cancer cells. This change not only supports tumor growth but also promotes resistance to therapeutic interventions (Wang et al., 2025).

The therapeutic potential of targeting both histone and non-histone lactylation is significant. By inhibiting the enzymes responsible for lactylation, or by modulating the signaling pathways that lead to lactate production, researchers can develop innovative approaches to treat pulmonary diseases and cancers characterized by metabolic dysregulation.

Correlation Between Lactate Metabolism and Inflammatory Diseases

Lactate metabolism is intricately linked to inflammatory diseases, particularly in the lungs. Elevated lactate levels in the context of pulmonary diseases can exacerbate inflammatory responses, leading to tissue damage and disease progression. The relationship between lactate accumulation and lysine lactylation provides a mechanistic understanding of how metabolic changes can influence inflammation.

Studies have shown that in conditions such as asthma and pulmonary fibrosis, increased lactate production correlates with heightened histone lactylation, which in turn drives the expression of pro-inflammatory cytokines (Wang et al., 2025). This feedback loop underscores the potential of targeting lactate metabolism and lactylation as therapeutic strategies for managing inflammatory lung diseases.

The emerging field of lysine lactylation research presents exciting opportunities for novel therapeutic interventions in pulmonary diseases and cancer. Future studies should focus on the following areas:

Identification of Lactylation Enzymes: Understanding the enzymes responsible for adding and removing lactyl groups (writers and erasers) can lead to the development of specific inhibitors that modulate lactylation levels in diseased tissues.
Clinical Trials: Investigating the efficacy of lactylation-targeted therapies in clinical settings, especially for lung cancer and inflammatory diseases, will be crucial to establish their therapeutic potential.
Metabolic Reprogramming: Exploring the relationship between metabolic reprogramming and lysine lactylation can provide insights into how to manipulate metabolic pathways to prevent or treat diseases.
Biomarker Development: Identifying specific lactylation patterns as biomarkers for early detection and monitoring of disease progression could enhance diagnostic accuracy and treatment efficacy.
Interdisciplinary Approaches: Collaborations between molecular biologists, oncologists, and pulmonologists will be essential to translate findings from basic research into clinical applications.

FAQ

What is lysine lactylation?
Lysine lactylation is a post-translational modification where a lactyl group is added to lysine residues in proteins, influencing their function and gene expression.

How does lysine lactylation affect pulmonary diseases?
Lysine lactylation is linked to metabolic reprogramming in lung diseases, influencing inflammation and cancer progression by modifying the expression of key genes.

What are the potential therapeutic implications of targeting lysine lactylation?
Targeting lysine lactylation could lead to novel therapies that inhibit tumor growth, reduce inflammation, and improve patient outcomes in pulmonary diseases and cancer.

Are there specific enzymes involved in lysine lactylation?
Yes, enzymes known as “writers” add lactyl groups to proteins, while “erasers” remove them, playing crucial roles in regulating lysine lactylation levels.

What future research directions are needed for lysine lactylation?
Future research should focus on understanding the enzymes involved in lactylation, conducting clinical trials, exploring metabolic pathways, and developing biomarkers.

References

Wang, S., Zheng, H., Zhao, J., & Xie, J. (2025). Role of lysine lactylation in neoplastic and inflammatory pulmonary diseases (Review). International Journal of Molecular Medicine. Retrieved from https://pubmed.ncbi.nlm.nih.gov/11913435/
Additional references will be expanded as the field evolves.